The Expert Committee recommended the addition of the fixed-dose combination of glecaprevir + pibrentasvir to the core list of the EML for the treatment of adult patients with chronic hepatitis C virus infection, based on evidence of pan-genotypic effectiveness and an acceptable safety profile. The Committee noted that this combination is one of three pan-genotypic combinations recommended in the current WHO guidelines for treatment of hepatitis C and is suitable for use in patients with or without compensated cirrhosis.
The Committee noted that the manufacturer and the Medicines Patent Pool (MPP) have entered into a licensing agreement for this product to accelerate access in 99 LMICs. However, the Committee noted with concern that some LMICs with a high burden of hepatitis C are not included in this agreement and encouraged the manufacturer and the MPP to address this issue to ensure patients in these high-burden countries have equitable access.
The Committee recommended that the hepatitis C medicines section of the Model List be amended to differentiate between pangenotypic (glecaprevir + pibrentasvir, sofosbuvir + daclatasvir and sofosbuvir + velpatasvir ), non-pangenotypic direct acting antivirals, and other antivirals for hepatitis C. The pangenotypic regimens should be considered as therapeutically equivalent to facilitate selection and procurement by countries at national level.
The Expert Committee then considered whether it was appropriate to delete non-pangenotypic treatments for hepatitis C, and recommended the deletion of simeprevir, whose place in therapy was now superceded by the pan-genotypic options. The Committee recommended that other non-pangenotypic treatments could be considerd for deletion from the EML in the future.
The application requested addition of the fixed-dose combination of glecaprevir + pibrentasvir to the core list of the EML for the treatment of adult patients with chronic hepatitis C virus infection, genotypes 1 to 6.
Neither this fixed-dose combination (FDC) nor its individual components have been previously considered by the Expert Committee for addition to the EML.
Public health relevance
Globally in 2015, it was estimated that 71 million persons were living with chronic HCV infection and nearly 400 000 died from cirrhosis or hepatocellular cancer.
The Global health sector strategy on viral hepatitis was endorsed by the World Health Assembly in 2016 and proposes the elimination of viral hepatitis as a public health threat by 2030 by achieving a 90% reduction in incidence and a 65% reduction in mortality. This requires 90% of infection persons to be diagnosed, and 80% of diagnosed persons to be treated (1).
In Phase II and III registrational studies, glecaprevir + pibrentasvir has shown high sustained viral response rates at 12 weeks (SVR12) across all hepatitis C genotypes and in key patient sub-populations (patients with chronic kidney disease, organ transplant recipients, patients coinfected with HIV and patients with compensated cirrhosis).
The application described SVR12 rates greater than 95% for all treated genotypes.
Among all GT1–6-infected subjects who received the recommended duration of treatment with glecaprevir + pibrentasvir, regardless of renal function, cirrhosis status, presence of HIV co-infection, treatment naive or treatment experienced, 97.4% (1252/1287) achieved SVR12 (2).
High SVR12 rates were also reported for GT1–6-infected subjects in key patient sub-populations.
The application described the findings of two randomized, Phase III, open-label studies that evaluated the safety and effectiveness of glecaprevir + pibrentasvir compared to sofosbuvir + ribavirin in Japanese patients with HCV GT2 (CERTAIN-2, Study M15-828) (3), and compared to sofosbuvir + daclatasvir in treatment-naive, non-cirrhotic HCV GT3 patients (ENDURANCE-3, Study M13-594) (4). In each study, glecaprevir + pibrentasvir was found to be non-inferior to the comparator treatments for the percentage of patients achieving SVR12.
Real-world data for glecaprevir + pibrentasvir also support the effectiveness demonstrated in the Phase 2 and 3 trials (5–9).
The application stated the safety assessment for glecaprevir + pibrentasvir in subjects with compensated liver disease (with or without cirrhosis) were derived from Phase II and III studies that evaluated 2369 subjects infected with GT 1, 2, 3, 4, 5 or 6 HCV who received treatment for 8, 12 or 16 weeks. The overall proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.1%. The most common adverse reactions were reported as headache (13.2%), fatigue (11.4%) and nausea (7.6%). These adverse reactions occurred at a similar frequency in patients receiving placebo or sofosbuvir + daclatasvir. Seven deaths were reported in the Phase II and III analysis set, none of which were considered to be related to the study drug. No apparent differences were observed in adverse event profiles by sex, race, ethnicity or baseline body mass index (BMI). The incidence of serious adverse events and adverse events of Grade 3 or higher was higher in patients aged 65 years or older compared to patients under 65 years. No other differences by age in the proportion of subjects reporting any adverse event, discontinuations or deaths were observed.
Real-world data for glecaprevir + pibrentasvir also support the safety demonstrated in clinical trials (5–9).
A systematic review of treatment options for chronic hepatitis C virus infection, genotypes 1–6 was conducted to inform the 2018 WHO Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection (10, 11). The review found that the proportion of patients treated with glecaprevir + pibrentasvir who achieved SVR12 ranged from 83% to 98%. GRADE assessments of the quality of evidence were high for GT1–3 and very low for GT4–6. For safety outcomes, the review assessed discontinuations due to adverse events (DAEs), serious adverse events (SAEs) and mortality. The pooled proportions for DAEs, SAEs and mortality for glecaprevir + pibrentasvir was 1%, 2% and 1%, respectively. GRADE assessments of the quality of evidence were moderate for DAEs and high for SAEs and mortality.
Cost / cost effectiveness
In a 2017 cost-effectiveness analysis in the United States, glecaprevir + pibrentasvir was shown to be a dominant pan-genotypic treatment option compared to current standard practices providing most favourable health outcomes at lowest cost (2). Health outcomes included quality-adjusted life-years (QALYs) and number needed to treat (NNT) to achieve a QALY, SVR or avoid an adverse liver event. In this analysis, glecaprevir + pibrentasvir was compared to two treatment strategies: (i) sofosbuvir + ledipasvir for GTs 1 and 4, and sofosbuvir + velpatasvir for GTs 2, 3, 5 and 6; and (ii) grazoprevir + elbasvir for GTs 1 and 4, and sofosbuvir + velpatasvir for GTs 2, 3, 5 and 6. A 12-week regimen course of glecaprevir + pibrentasvir was assumed to cost US$ 27 929 USD (at 2017 wholesale acquisition drug costs). Cost-effectiveness results in other countries may vary based on the different pricing of glecaprevir + pibrentasvir and other DAAs.
The 2018 WHO Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection (1) recommend:
the use of pangenotypic direct-acting antiviral (DAA) regimens for the treatment of chronic HCV infection in persons aged 18 years and older (conditional recommendation, moderate quality evidence);
glecaprevir + pibrentasvir as a pangenotypic treatment option for adults with or without compensated cirrhosis.
Glecaprevir + pibrentasvir has marketing approval and is commercially available in 58 countries globally. AbbVie and the Medicines Patent Pool have entered into a royalty-free licensing agreement to accelerate access in 99 LMICs. Through this agreement, AbbVie will allow WHO prequalified generic manufacturers to license, manufacture and supply generic versions. AbbVie is also considering the inclusion of glecaprevir + pibrentasvir on the WHO List of Prequalified Medicinal Products.
1. Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/273174/9789241550345-eng.pdf, accessed 29 September 2019.
2. Saab S, Parisé H, Virabhak S, Johnson S, Pinsky B, Sanchez Y. Pan‐genotypic hepatitis C treatment with glecaprevir/pibrentasvir achieves greatest improvements in quality‐adjusted life‐years and lifetime risk reductions in liver‐related morbidity and mortality vs standards of care: a cost‐utility analysis. Poster Abstract 1578. Hepatology. 2017;66(S1):843A.
3. Abbvie - M15-828 Clinical Study Report – Final. A Randomized, Open-Label, Active Comparator, Multicenter Study to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in Japanese Adults with Genotype 2 Chronic Hepatitis C Virus Infection (CERTAIN-2) [website]. (https://www.abbvie.com/content/dam/abbvie-dotcom/clinical-trials/glecaprevir_pibrentasvir_M15-828_Redacted.pdf, accessed 29 September 2019).
4. Abbvie - M13-594 Clinical Study Report - Final. A Randomized, Open-Label, Active-Controlled, Multicenter Study to Compare Efficacy and Safety of ABT-493/ABT-530 to Sofosbuvir Co-Administered with Daclatasvir in Adults with Chronic Hepatitis C Virus Genotype 3 Infection (ENDURANCE-3) [website]. (https://www.abbvie.com/content/dam/abbvie-dotcom/clinical-trials/glecaprevir_pibrentasvir_M13-594_Redacted.pdf, accessed 29 September 2019).
5. Belperio P, Shahoumian T, Loomis T, Mole L, Backus LI. Real‐World Effectiveness of Glecaprevir/Pibrentasvir in 1,941 Patients with Hepatitis C Genotypes 1 through 4. Poster Abstract 703. Hepatology. 2018;68(S1):417A-418A.
6. Curry MP, Bacon BR, Flamm SL, Marks M, Milligan S, Tsai NCS et al. Preferences in Clinical Practice with Glecaprevir/Pibrentasvir (GLE‐PIB), Ledipasvir/ Sofosbuvir (LDV‐SOF), and Sofosbuvir/Velpatasvir (SOF‐VEL); Data from the Trio Network. Poster Abstract 678. Hepatology. 2018;68(S1):402A.
7. D'Ambrosio R, Pasulo L, Puoti M, Vinci M, Schiavini M, Lazzaroni S et al. Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C. J Hepatol. 2019; 70(3):379–387.
8. Puigvehi M, Albillos A, Viu A, Hernandez Guerra MN, Fernandez I, Prieto M et al. Effectiveness and Safety of Glecaprevir/Pibrentasvir for the Pangenotypic Treatment of Chronic Hepatitis C: Results from a Spanish Cohort (Hepa‐C). Poster Abstract 601. Hepatology. 2018;68(S1):657A.
9. Wiegand J, Naumann U, Stoehr A, Sick C, John C, Teuber G et al. Glecaprevir/Pibrentasvir for the Treatment of Patients with Chronic Hepatitis C Virus Infection: Updated Real‐World Data from the German Hepatitis C‐Registry. Poster Abstract 611. Hepatology. 2018;68(S1):364A.
10. Zoratti M. Web Annex 3.1. Adult hepatitis C virus treatment systematic review. In: Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/277215/WHO-CDS-HIV-18.36-eng.pdf, accessed 29 September 2019.
11. Zoratti M. Web Annex 3.2. Adult hepatitis C virus treatment systematic review: supporting evidence. In: Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/277216/WHO-CDS-HIV-18.37-eng.pdf, accessed 29 September 2019.